Emerging evidence indicates that immune and inflammatory cytokine pathways promote the development and progression of lymphoma, however the molecular mechanisms are poorly defined. The TNF receptor superfamily member, HVEM (herpesvirus entry mediator; TNFRSF14) and the Ig superfamily protein, BTLA (B and T lymphocyte attenuator) form a novel signaling network that regulates lymphocyte activation and proliferation. Importantly, recent genetic analyses of human lymphomas and related hematologic malignancies revealed frequent somatic mutations in HVEM and BTLA that are associated with poor prognosis. Our research provides new evidence that somatic point mutations in HVEM identified in human lymphomas specifically alter ligand engagement, potentially affecting intrinsic NF?B survival pathways and immune regulatory mechanisms. We identified a novel transcriptional regulatory pathway that down modulates BTLA that may account for the suppression of BTLA expression in B and T-lymphoma cells. The HVEM-BTLA pathway, although well-recognized in host defense, is poorly defined in the context of cancer. The proliferation inhibiting functions and frequent somatic mutations suggest that the HVEM-BTLA pathway may serve as a check-point for the development and progression of hematologic malignancies. In this project, the molecular mechanisms of the dysregulation of the HVEM and BTLA pathway in human lymphoma lines will be determined. The affect of the HVEM-BTLA pathway is examined in mouse models of B cell malignancies. An array of antibody and receptor-based agonists and antagonists of the HVEM-BTLA related cytokines have been developed, and mice with null and conditional gene deletions in HVEM and BTLA are available to complement the results in human lymphoma cells. Together, these aims integrate molecular defects in the HVEM-BTLA pathways in human lymphoma with in vivo models to evaluate this pathway in the development and progression of lymphoma and leukemia, providing the rationale to therapeutically manipulate these pathways. PUBLIC HEALTH RELEVANCE: This project examines how cellular communication proteins called cytokines that normally control the growth of white blood cells change when their genes are mutated in lymphoma and leukemia. The experiments here will determine whether potential drugs directed at these cytokines halt the growth of lymphoma and leukemia.